CA2841237C - Modulateurs des recepteurs de quinolinylglucagon - Google Patents

Info

Publication number

CA2841237C

CA2841237C CA2841237A CA2841237A CA2841237C CA 2841237 C CA2841237 C CA 2841237C CA 2841237 A CA2841237 A CA 2841237A CA 2841237 A CA2841237 A CA 2841237A CA 2841237 C CA2841237 C CA 2841237C

Authority

CA

Canada

Prior art keywords

methyl

ylamino

butyl

quinolin

mmol

Prior art date

2011-07-22

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Fee Related

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• 102100040890 Glucagon receptor Human genes 0.000 title claims description 21
• 108010063919 Glucagon Receptors Proteins 0.000 title claims description 20
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 170
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 44
• 150000003839 salts Chemical class 0.000 claims abstract description 41
• 208000035475 disorder Diseases 0.000 claims abstract description 23
• 238000011282 treatment Methods 0.000 claims abstract description 23
• 201000010099 disease Diseases 0.000 claims abstract description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 87
• -1 chloro, methyl Chemical group 0.000 claims description 46
• 125000001153 fluoro group Chemical group F* 0.000 claims description 32
• 235000019260 propionic acid Nutrition 0.000 claims description 26
• DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 25
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 25
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
• 239000001257 hydrogen Substances 0.000 claims description 21
• 229910052739 hydrogen Inorganic materials 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
• 208000008589 Obesity Diseases 0.000 claims description 17
• 235000020824 obesity Nutrition 0.000 claims description 17
• 206010012601 diabetes mellitus Diseases 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 16
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 13
• 239000003085 diluting agent Substances 0.000 claims description 12
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
• BVJDGKQCWAYVEZ-UHFFFAOYSA-N 3-[[4-[3-methyl-1-[(3-methylquinolin-2-yl)amino]butyl]benzoyl]amino]propanoic acid Chemical compound N=1C2=CC=CC=C2C=C(C)C=1NC(CC(C)C)C1=CC=C(C(=O)NCCC(O)=O)C=C1 BVJDGKQCWAYVEZ-UHFFFAOYSA-N 0.000 claims description 8
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 7
• KQBQZWBDDOVGRD-UHFFFAOYSA-N 3-[[4-[1-[(3-methylquinolin-2-yl)amino]butyl]benzoyl]amino]propanoic acid Chemical group N=1C2=CC=CC=C2C=C(C)C=1NC(CCC)C1=CC=C(C(=O)NCCC(O)=O)C=C1 KQBQZWBDDOVGRD-UHFFFAOYSA-N 0.000 claims description 7
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
• MNPUWRWCAJUYKB-UHFFFAOYSA-N 3-[[4-[(3,3-dimethylcyclobutyl)-[(6-fluoroquinolin-3-yl)amino]methyl]benzoyl]amino]propanoic acid Chemical compound C1C(C)(C)CC1C(C=1C=CC(=CC=1)C(=O)NCCC(O)=O)NC1=CN=C(C=CC(F)=C2)C2=C1 MNPUWRWCAJUYKB-UHFFFAOYSA-N 0.000 claims description 4
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
• 229910052799 carbon Inorganic materials 0.000 claims description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
• 125000005843 halogen group Chemical group 0.000 claims description 4
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
• SPIQGMFFSBEHRX-UHFFFAOYSA-N 3-[[4-[3-methyl-1-[[6-(trifluoromethyl)quinolin-2-yl]amino]butyl]benzoyl]amino]propanoic acid Chemical compound C=1C=C2C=C(C(F)(F)F)C=CC2=NC=1NC(CC(C)C)C1=CC=C(C(=O)NCCC(O)=O)C=C1 SPIQGMFFSBEHRX-UHFFFAOYSA-N 0.000 claims description 3
• UVDZJWKHYXRRRH-UHFFFAOYSA-N 3-[[4-[3-methyl-1-[[7-(trifluoromethyl)quinolin-2-yl]amino]butyl]benzoyl]amino]propanoic acid Chemical compound C=1C=C2C=CC(C(F)(F)F)=CC2=NC=1NC(CC(C)C)C1=CC=C(C(=O)NCCC(O)=O)C=C1 UVDZJWKHYXRRRH-UHFFFAOYSA-N 0.000 claims description 3
• 230000009849 deactivation Effects 0.000 claims description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
• JHYVBNOMIUNRJS-UHFFFAOYSA-N 3-[[4-[(3,3-dimethylcyclobutyl)-[(3-methylquinolin-2-yl)amino]methyl]benzoyl]amino]propanoic acid Chemical compound CC1=CC2=CC=CC=C2N=C1NC(C=1C=CC(=CC=1)C(=O)NCCC(O)=O)C1CC(C)(C)C1 JHYVBNOMIUNRJS-UHFFFAOYSA-N 0.000 claims 3
• YZUWLDZGWNDIRB-UHFFFAOYSA-N 3-[[4-[(3,3-dimethylcyclobutyl)-[(6-fluoro-3-methylquinolin-2-yl)amino]methyl]benzoyl]amino]propanoic acid Chemical compound CC1=CC2=CC(F)=CC=C2N=C1NC(C=1C=CC(=CC=1)C(=O)NCCC(O)=O)C1CC(C)(C)C1 YZUWLDZGWNDIRB-UHFFFAOYSA-N 0.000 claims 3
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
• 102000051325 Glucagon Human genes 0.000 abstract description 30
• MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 abstract description 30
• 229960004666 glucagon Drugs 0.000 abstract description 30
• 108060003199 Glucagon Proteins 0.000 abstract description 29
• 239000000556 agonist Substances 0.000 abstract description 26
• 239000005557 antagonist Substances 0.000 abstract description 22
• 230000001404 mediated effect Effects 0.000 abstract description 5
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 328
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 255
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 183
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 180
• 239000000543 intermediate Substances 0.000 description 149
• 239000000243 solution Substances 0.000 description 117
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 117
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 116
• 239000000203 mixture Substances 0.000 description 115
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 114
• 238000006243 chemical reaction Methods 0.000 description 87
• 238000005160 1H NMR spectroscopy Methods 0.000 description 79
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 78
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 72
• 239000007787 solid Substances 0.000 description 70
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 58
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 55
• 229910052938 sodium sulfate Inorganic materials 0.000 description 55
• 235000011152 sodium sulphate Nutrition 0.000 description 55
• 239000012044 organic layer Substances 0.000 description 54
• 238000000746 purification Methods 0.000 description 53
• 239000003607 modifier Substances 0.000 description 42
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
• 239000002253 acid Substances 0.000 description 37
• 239000000741 silica gel Substances 0.000 description 37
• 229910002027 silica gel Inorganic materials 0.000 description 37
• 239000007832 Na2SO4 Substances 0.000 description 35
• 239000010410 layer Substances 0.000 description 35
• 238000000034 method Methods 0.000 description 35
• 230000002829 reductive effect Effects 0.000 description 35
• 239000003112 inhibitor Substances 0.000 description 34
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
• 230000014759 maintenance of location Effects 0.000 description 32
• 238000003818 flash chromatography Methods 0.000 description 28
• 239000003921 oil Substances 0.000 description 27
• 235000019198 oils Nutrition 0.000 description 27
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 26
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 26
• 239000002904 solvent Substances 0.000 description 26
• 239000011541 reaction mixture Substances 0.000 description 25
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 23
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 22
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
• 239000000706 filtrate Substances 0.000 description 20
• 238000004808 supercritical fluid chromatography Methods 0.000 description 17
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 15
• 125000004494 ethyl ester group Chemical group 0.000 description 15
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
• 238000004007 reversed phase HPLC Methods 0.000 description 14
• 102000004877 Insulin Human genes 0.000 description 13
• 108090001061 Insulin Proteins 0.000 description 13
• 239000012267 brine Substances 0.000 description 13
• 239000013058 crude material Substances 0.000 description 13
• 229940125396 insulin Drugs 0.000 description 13
• 239000002002 slurry Substances 0.000 description 13
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
• 125000000217 alkyl group Chemical group 0.000 description 12
• 239000001569 carbon dioxide Substances 0.000 description 12
• 229910002092 carbon dioxide Inorganic materials 0.000 description 12
• 239000003480 eluent Substances 0.000 description 12
• 241001465754 Metazoa Species 0.000 description 11
• 239000000463 material Substances 0.000 description 11
• 238000010992 reflux Methods 0.000 description 11
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• 239000003472 antidiabetic agent Substances 0.000 description 10
• 239000007864 aqueous solution Substances 0.000 description 10
• 239000008103 glucose Substances 0.000 description 10
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
• 235000019341 magnesium sulphate Nutrition 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 235000017557 sodium bicarbonate Nutrition 0.000 description 10
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
• IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 9
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
• 235000011114 ammonium hydroxide Nutrition 0.000 description 9
• 229940125708 antidiabetic agent Drugs 0.000 description 9
• 238000001816 cooling Methods 0.000 description 9
• 229940079593 drug Drugs 0.000 description 9
• XPGRZDJXVKFLHQ-UHFFFAOYSA-N hydron;methyl 3-aminopropanoate;chloride Chemical compound Cl.COC(=O)CCN XPGRZDJXVKFLHQ-UHFFFAOYSA-N 0.000 description 9
• 229920006395 saturated elastomer Polymers 0.000 description 9
• 201000001421 hyperglycemia Diseases 0.000 description 8
• 238000002360 preparation method Methods 0.000 description 8
• 238000010898 silica gel chromatography Methods 0.000 description 8
• 238000003756 stirring Methods 0.000 description 8
• CIZXIQQLEOYMSQ-UHFFFAOYSA-N 3-bromo-7-methylquinoline Chemical compound C1=C(Br)C=NC2=CC(C)=CC=C21 CIZXIQQLEOYMSQ-UHFFFAOYSA-N 0.000 description 7
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
• 241000124008 Mammalia Species 0.000 description 7
• 208000001145 Metabolic Syndrome Diseases 0.000 description 7
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 7
• 150000001412 amines Chemical class 0.000 description 7
• 238000003556 assay Methods 0.000 description 7
• 239000002585 base Substances 0.000 description 7
• 210000004027 cell Anatomy 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• 238000009472 formulation Methods 0.000 description 7
• 239000008177 pharmaceutical agent Substances 0.000 description 7
• 102000005962 receptors Human genes 0.000 description 7
• 108020003175 receptors Proteins 0.000 description 7
• 239000011780 sodium chloride Substances 0.000 description 7
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
• 239000005711 Benzoic acid Substances 0.000 description 6
• 235000019270 ammonium chloride Nutrition 0.000 description 6
• 230000027455 binding Effects 0.000 description 6
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• 238000005859 coupling reaction Methods 0.000 description 6
• 239000012043 crude product Substances 0.000 description 6
• CPNCRYXKJNSJGV-UHFFFAOYSA-N ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C(=O)C1CC(C)(C)C1 CPNCRYXKJNSJGV-UHFFFAOYSA-N 0.000 description 6
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 6
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
• 150000004702 methyl esters Chemical class 0.000 description 6
• 229910052757 nitrogen Inorganic materials 0.000 description 6
• 238000005897 peptide coupling reaction Methods 0.000 description 6
• 239000000047 product Substances 0.000 description 6
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